Lycoposerramine-S

 

Lycoposerramine-S

Angew. Chem. Int. Ed. 2012, 51, 11824

TN. Shimada, Y. Abe, S. Yokoshima, T. Fukuyama*

The retrosyntheses of Lycoposerramine S beings with the deprotection of the Boc group, N-methylation (para-formaldehyde and sodium cyanoborohydride) and deprotection of the nosyl (4-nitrobenzenesulfonamide) group from 13.  Compound 13 was prepared from 12 by bis-mesylating the bis-alcohol and then treating it with 4-nitrobenzulfonamide using Cs₂CO₃ as the base.  This is the first time I saw the use of 4-nitrobenzenesulfonamide to install the nosyl group.  Compound 12 was prepared from hydroxyalkene 11 by first activating the hydroxyl group as thionocarbonate and then cyclizing it under free-radical-conditions to the alkene group.  Alkene 11 was prepared by dehydrating the secondary alcohol in 10.  Compound 10 was prepared by the reduction of the ketone group and reductive removal of the chiral auxiliary in compound 9, which in turn, was prepared by reacting aldehyde 7 with amine 8.  The reaction between 7 and 8 is the key step of this synthesis.  Aldehyde group reacts with the amine to generate the amine which then gets polarized and undergoes a 1,3-dipolar addition with the alkene group thereby completing the bicyclic-ring formation as shown in the graphic below the main scheme.  Aldehyde 7 was prepared by oxidation of alcohol 6, which in turn was derived from vinyl-iodide 4 by going through an initial metal-halogen exchange followed by addition of lactone 5.  Vinyl-iodide 4 was prepared from symmetrical alkyne 3, which was easily obtained from alkyne 1.

Overall, this is a very interesting synthesis from the Fukuyama group in the sense that the product is formed from rather simple looking precursors and is made with the minimum of fuss.  The cycloaddition step is quite noteworthy.

 

 

Voacangalactone

Voacangalactone

Organic Letters 2012, 14, 5800

M. Harada, K. N. Asaba, M. Iwai, N. Kogure, M. Kitajima, and H. Takayama*

The retrosynthesis of Voacangalactone A begins with the reduction of keto-amide group in 17 to reveal the amine functionality.  Compound 17 was prepared by cyclization of the keto-ester on the deprotected amine, which in turn came by acylation of oxalyl chloride on indole 16.  The indole ring was closed by using Utimoto’s protocol employing NaAuCl₄.2H₂O as the oxidant on alkyne 15, which was prepared by a Sonogashira reaction between 2-iodo-4-methoxyaniline and alkyne 14.  Here, CuSO₄ was used as the copper source – no doubt reduced to Cu(I) by Na-ascorbate.  I had never seen being used in Sonogashira reaction, but this is referenced from the work of Bag, S. S. et al. Org. Chem. 2011, 76, 2332–2337.  Going further back, the alkyne 14 was prepared from alcohol 13 using standard transformations.  Compound 13’s precursor was iodo-alcohol 12, which came from acid 11.  Acid 11 was prepared by an iodo-lactonization-hydrolysis sequence on diester 10.  This is a really nice step as it establishes the lactone-ring elegantly and also allows differentiation of the oxidation states of the pendant carbon.  The bicyclic-amine 10 was closed by alkylating Cbz-amine 9.  Compound 9 is a penta-substituted cyclohexene and thus it is not surprising that an asymmetric Diels-Alder reaction was used to prepare it.  Its immediate precursor is the chiral auxiallary containing intermediate 8, which comes by a Diels-Alder reaction between dimethyl 2-methylenemalonate and diene 7.  This Diels-Alder reaction is between an electron-rich diene and an electron-deficient dienophile.  No wonder, it even goes at room temperature.  It is also completely regioselective – again due to the relative electronics of the reactants.  The absolute stereochemistry is driven by the chiral auxiallary.  This is the key step of this synthesis.  The diene was prepared by a Cu-mediated amination of vinyl-iodide 5.  Adjustment of the carbon oxidation states meant that 5 came from conjugated ester 4, which came from aldehyde 3 by a Wittig reaction.  Aldehyde 3 was prepared by reduction-oxidation sequence on acid 2, which was prepared by decarboxylation/hydrolysis of diester 1.  Diester 1 was prepared by alkylation of diethyl ethylmalonate.

 

Overall, a really nice synthesis.

 

 

 

 

Aspercyclides A & B

Aspercyclides A  & B

Organic Letters 2012, 14, 4290-4292

T. Yoshino, I. Sato*, M. Hirama

The retrosyntheses of Aspercyclides A and B begin with a common advanced intermediate 8.  For aspercyclide A (which has an aldehyde group), the hydromethyl in 8 is first oxidized using manganese oxide and the benzylether is deprotected using boron trichloride.  For aspercyclide B (which has the hydroxymethyl group), the benzylether group is deprotected using boron trichloride.  Thus, with one advanced intermediate, they are able to get two natural products.  Intermediate 8 is prepared by a very interesting selective oxidative phenol-aryl bonding.  There are two phenolic groups present in 7 (the precursor to 8) and only one of them is oxidized and undergoes a ring-closure reaction with the other aryl ring.  The authors explain this chemo-selectivity on the relative electron richness of the two phenols.  One has alkyl substituents, while the other has a carbonyl group on it – the more electron rich phenol (with alkyl substituents) gets oxidized and reacts with the other.  They even did a side experiment where they took two phenols – one with alkyl groups and the other with carbonyl.  Only the one with the alkyl groups reacts with phenyl iodoacetate!  Very nice!! Moving along backwards, intermediate 7 comes by a slightly convoluted protection/deprotection series of steps, but it again has some interesting selectivity.  Intermediate 7 has the hydroxymethyl group protected as the TBS ether and with two open phenol groups.  All three were initially protected as TBS ether, but the two phenol hydroxyl groups were deprotected selectively by TBAF (i.e. TBAF left the hydroxymethyl TBS ether intact!)  Their precursor was formed by the acetonide deprotection of 6.  Intermediate 6 comes by esterification reaction between alcohol 4 and methyl ester 5.  Compound 4 was derived from a Heck reaction between alkene 3 and aryl iodide 2.  Alkene 3 was prepared by attack of butyl anion (from nBuLi) on epoxide formed by the Sharpless epoxidation (and the benzyl ether protection) on penta-1,4-dien-3-ol.  Also interesting are the preparation of intermediates 5 and 2 from a common precursor – 1.  Thus compound 5 is prepared by palladium catalyzed methyl zinc  substitution on iodide 1, whereas compound 2 is prepared by deprotection of the acetonide in 1, followed by reduction of the acid to the alcohol and the re-formation of the acetonide ring. 

Overall, this is a very neat synthesis and has some very interesting selective transformations (selective TBS ether deprotection & selective phenolic oxidative cyclization).  

 

(-)-Huperzine A

 

 

(-)-Huperzine A

Organic Letters, 2012, 14, 4446-4449

R. Ding, B.-F. Sun, G.-Q. Lin

The retrosynthesis of (-)-Huperzine begins with an acid-mediated rearrangement along with dehydration to install the two double bonds.  The conditions for these two transformations took a while to develop as there were other side-reactions occurring as well.  The rearrangement is especially noteworthy since it allows the use of (R)-pugelone as the starting material.  The tertiary alcohol in 10 is formed by ethyl Grignard addition to the ketone 9, which in turn comes by oxidation of diastereomeric alcohols 8.  An elegant Heck-reaction forms the bicyclic structure from 7.  This shows the two parts of the molecule – the “cyclohexene” and the “pyridine” parts – linked through a methylene group.  Thus, alcohol 7 comes by reduction of ketone 6, which is setup to be derived by an enolate addition of ketone 4 on bromide 5.  Compound 4 is derived by a Buchwald-type coupling of Boc amine on enol triflate 3.  The enol triflate 3 is derived from 2, which is easily accessible from (R)-pulegone.

(-)-KAITOCEPHALIN

 

 

(-)-KAITOCEPHALIN

Organic Letters, 2012, 14, 1644-1647

K. Takahashi, D. Yamaguchi, J. Ishihara, S. Hatakeyama*

The retrosythesis of (-)-Kaitocephalin begins with unmasking all the acid groups by oxidizing phenyl and carbon-carbon double bonds while the amino and alcohol groups are also simultaneously generated by deprotecting the oxazolidone ring of 14.  This is very rarely seen in total syntheses as people generally shy away from such strong oxidations towards the end of the synthesis.  So, keeping a benzene ring and carbon-carbon double bonds are “masked acids” is a useful disconnection.  Compound 14 predictably comes from acid chloride 13 and deprotected form of amine 12.  Compound 12 is formed by a stereoselective intramolecular C-H amination in 11 mediated by a Rh catalyst.   This is a neat way of establishing a crucial stereocenter.  Compound 11 comes from protected alcohol 10.  Compound 10 is generated by an intramolecular addition of a carbamate on cyclic sulfamate 9, which comes from another stereoselective intramolecular C-H amination of sulfonamide 8.  This step is very similar to the preparation of 12 from 11 – sulfonyl versus and carbonyl and also a different ligand is used in the Rh catalyst.  Compound 8 comes from protected alcohol 7, which in turn is prepared by a Overman rearrangement reaction of alcohol 6.  This step establishes the quaternary spiro stereocenter.  Compound 6 is formed by a Suzuki reaction between alkyl boronate ester and vinyl iodide 5.  This comes from protection-deprotection of alcohol 4 whose precursor is ketone 3.  Ketone 3 comes from the iodination of 2, which is derived from alcohol 1, by an enzyme-mediated stereoselective oxidation.

 

(-)-Huperzine A

(-)-Huperzine A

Organic Letters, 2012, 14, 4446-4449

R. Ding, B.-F. Sun, G.-Q. Lin

The retrosynthesis of (-)-Huperzine begins with an acid-mediated rearrangement along with dehydration to install the two double bonds.  The conditions for these two transformations took a while to develop as there were other side-reactions occurring as well.  The rearrangement is especially noteworthy since it allows the use of (R)-pugelone as the starting material.  The tertiary alcohol in 10 is formed by ethyl Grignard addition to the ketone 9, which in turn comes by oxidation of diastereomeric alcohols 8.  An elegant Heck-reaction forms the bicyclic structure from 7.  This shows the two parts of the molecule – the “cyclohexene” and the “pyridine” parts – linked through a methylene group.  Thus, alcohol 7 comes by reduction of ketone 6, which is setup to be derived by an enolate addition of ketone 4 on bromide 5.  Compound 4 is derived by a Buchwald-type coupling of Boc amine on enol triflate 3.  The enol triflate 3 is derived from 2, which is easily accessible from (R)-pulegone.